Granatiero V, Giorgio V, Calì T, Patron M, Brini M, Bernardi P, Tiranti V, Zeviani M, Pallafacchina G, De Stefani D, Rizzuto R
Many layers of compensation potentially exist, to compensate for mutations in mitochondrial DNA: mtDNA biogenesis, modifications to transcription, translation, diffusive complementation and so on.
This study aims to determine how one such mutation is compensated for. The authors use primary skin fibroblasts from patients carrying a (phenotypically mild) heteroplasmic point mutation in a mitochondrially-encoded subunit of complex I (13514A>G, affecting the ND5 subunit).
They observed a higher rate of mitochondrial recycling in mutant cells, via mitophagy. In addition, the mutants had a lowered calcium uptake into the mitochondria when exposed to histamine (which causes calcium release from the endoplasmic reticulum into both the cytoplasm and mitochondria), which was associated with higher AMPK levels. Using split GFP technology, they showed that the mutants possessed fewer mitochondrial-ER contact sites.
To determine causality, the authors manipulated mitochondrial calcium uptake by overexpressing components of the mitochondrial calcium uniporter, and also treating cells with Kaempferol. These interventions recovered the calcium response to histamine, reduced AMPK levels and reduced autophagosome number. This intervention, however, reduced cell viability; presumably because of a lowered mitophagy rate.
Thus, the authors propose that, in this system, the cell reduces mitochondrial calcium uptake to increase mitochondrial recycling. They suggest this is mediated via AMPK, which senses the AMP/ATP ratio. This acts as a pro-survival mechanism, in mutated cells.
Thoughts: AMPK correlates with the recycling rate, but it would be interesting to see whether an intervention altering AMPK levels, alters mitophagy rate in the expected way, to demonstrate this causal link?
I wonder whether these cells have lowered respiration and generate less ATP, because of their mutation...? This could then explain their increased AMPK levels, and perhaps also their increased mitophagy rate? Maybe perturbing cells to uptake more calcium, causes more flux through the respiratory chain and so alleviates energy deficiency and lowers mitophagy, but a mutated complex I causes higher levels of ROS to give a pro-apoptosis signal? Interesting system!